NeuroRegen: In-Silico Design of Dual-Action Intranasal Nanoparticle Therapy for Alzheimer’s Disease

Video Transcript:

Today, Alzheimer’s disease affects over 55 million people worldwide - yet approved treatments do not focus on the underlying mechanisms of the disease, cause toxic side effects, and cost over $30,000 a year.

Hello, my name is Rahul Rao, and I’m Vivaan Kar.

We developed a novel dual-action strategy combining two compounds — Tropoflavin and EF-24 — to directly target the biological mechanisms driving Alzheimer's neurodegeneration.

Across four computational experiments our compounds demonstrated stronger and more stable binding to Alzheimer's proteins than currently approved drugs. Intransanal delivery achieved over 600 times greater brain concentration than oral administration, with no major systemic side effects.

We also conducted an in-vitro synthesis of PLGA nanoparticles containing our compounds at the University of Toronto’s MaRs Research Lab.

NeuroRegen, a self-administered nasal spray, makes effective Alzheimer's treatment accessible and affordable across the globe.

Current therapies delay progression; this approach targets the disease at its source.

Alzheimer’s Disease Overview

Alzheimer’s disease (AD) affects over 50 million people globally - projected to double by 2050. A progressive, irreversible neurological disorder, AD gradually weakens memory, cognition, and the ability to perform simple tasks.

Causes

On the biological level, multiple mechanisms work together to destroy neurons and disrupt communication in AD:

1. Amyloid-Beta Plaques

Accumulate between neurons, disrupt communication, cause inflammation. Overstimulate NMDA receptors, leading to calcium imbalance and neuronal stress.

2. Tau Neurofibrillary Tangles

Tau becomes hyperphosphorylated, detach from microtubules, and aggregate into tangles. This destabilizes neuronal transport systems, blocks nutrient flow and causes cellular collapse.

3. Impaired BDNF-TrkB Signaling

Brain-Derived Neurotrophic Factor (BDNF) is essential for neuronal health and memory formation. It activates through its high affinity receptor TrkB. In AD, BDNF production is reduced, and neurons become vulnerable to degeneration.

Problem

Current treatments approved for AD primarily alleviate symptoms, but do not target underlying biological mechanisms. They fall into two categories: symptomatic therapies, which offer modest cognitive improvement for 6-12 months, and anti-amyloid antibodies, which clear amyloid-beta plaques but remain ineffective in later stages of AD. Both treatments carry serious side effects and high costs.

Objectives

Develop an effective multi-target, disease-modifying treatment with reduced side effects, and enhanced bioavailability.

Evaluate molecular binding and stability using computational modelling.

Assess pharmacokinetics and bioavailability.

Design and synthesize targeted treatment.

Novel Approach

NeuroRegen employs a dual-action strategy (EF-24 inhibits tau aggregation and Tropoflavin restores BDNF-TrkB signaling) delivered via PLGA nanoparticles for controlled release, minimized toxicity, and accessible intranasal administration.

To validate our approach, we performed four in-silico computational simulations and one in-vitro synthesis experiment. Procedures were conducted in triplicate.

Hypothesis

It was hypothesized that an intranasal PLGA nanoparticle formulation containing Tropoflavin and EF24 would demonstrate superior molecular targeting, enhanced brain delivery, and reduced systemic toxicity compared to current AD treatments.

Molecular Docking

Rationale: To evaluate binding strength and specificity of Tropoflavin and EF24 to AD related proteins.

Protein structures (TrkB, Tau, GSK-3β) from RCSB protein bank were prepared in UCSF ChimeraX

Ligand structures (Tropoflavin, EF24, Donepezil, Memantine) were downloaded from PubChem.

Docking simulations were performed using SwissDock.

Predicted binding energies were recorded.

Molecular Dynamics

Rationale: To evaluate binding stability in physiological conditions over time.

Protein structures from RCSB protein bank were prepared in UCSF ChimeraX

Ligand structures were downloaded from PubChem.

Protein-ligand structures were constructed in isotonic-physiological conditions using CharmmGUI.

Using GROMACS on Google Colab, each protein-ligand simulation was run.

Protein backbone RMSD and mean hydrogen bond count were recorded.

ADMET Analysis

Rationale: To assess blood-brain barrier penetration, solubility and toxicity of treatments.

SMILES codes of compounds were obtained from PubChem.

ADME properties were analyzed using SwissADME (lipophilicity, solubility, BBB-permeability, drug-likeness).

Toxicity was predicted using admetSAR 2.0 (Ames, hepatotoxicity, LD50, general safety).

Pharmacokinetic Simulations

Rationale: To compare brain delivery efficiency of intranasal vs oral administration for Tropoflavin and EF24.

Compound profiles and population models were created in PK-Sim

Oral and intranasal administration simulations were conducted. Brain concentrations over 24 hours were recorded (Cmax, Tmax, AUC).

Nanoparticle Synthesis & Characterization

Rationale: To evaluate nanoparticle characteristics for pharmaceutically viable delivery via olfactory pathway.

PLGA nanoparticles containing drug compounds were synthesized using an oil-in-water emulsion evaporation procedure.

Suspension was suspended within an isotonic saline solution to isolate nanoparticles.

Particle size, PDI and zeta potential were measured using dynamic light scattering (DLS).

All four computational experiments and the in-vitro synthesis support all hypotheses.

Collectively, these results provide fundamental computational and experimental evidence that NeuroRegen represents a pharmacologically viable, safe, accessible, and disease-modifying alternative to current AD treatments.

Molecular Docking

Tropoflavin demonstrated the strongest predicted binding affinity to the TrkB receptor (-9.079 kcal/mol), outperforming Donepezil (−7.796 kcal/mol) and Memantine (−6.036 kcal/mol). EF24 demonstrated strong binding to Tau (−5.068 kcal/mol) and GSK-3β (−7.796 kcal/mol), outperforming Donepezil and Memantine. Each compound bound most effectively to its intended protein confirming the specificity of the multi-target design to treat underlying biological mechanisms of AD.

Molecular Dynamics

Docking predictions were validated under dynamic physiological conditions across a 20-nanosecond simulation. Tropoflavin maintained stable TrkB binding (RMSD = 2.2Å, mean H-bonds = 3.2). EF24 demonstrated stable binding at Tau (RMSD = 2.6Å, mean H-bonds = 2.4) and GSK-3β (RMSD = 2.1Å, mean H-bonds = 3.1). Donepezil exhibited borderline or unstable binding across all targets; Memantine provided no meaningful stable binding at any AD-relevant protein. These results corroborate molecular docking findings and confirm that protein-ligand interactions remain stable over time in physiological conditions.

ADMET Analysis

Tropoflavin and EF24 demonstrated favourable blood-brain barrier permeability, drug-likeness, and optimal lipophilicity (LogP 2.35, 3.87), with acceptable LD50 values. Toxicity analyses confirmed that intranasal nanoparticle delivery bypasses first-pass metabolism, rendering any potential side effects from Tropoflavin or EF24 negligible. Donepezil exhibited excessive lipophilicity and mutagenic potential; Memantine showed poor solubility and systemic irritation, with mild toxicity.

Pharmacokinetic Simulations

Intranasal delivery resulted in a dramatically greater brain concentration compared to oral administration. Cmax increased 642x for Tropoflavin and 1155x for EF24. Tmax decreased from 2.75 hours to 0.05 hours for both compounds. AUC increased 1500x for Tropoflavin and 100x for EF24. These dramatic improvements suggest that oral delivery cannot achieve therapeutically relevant brain concentrations, and that the olfactory pathway is the most viable route for effective treatment.

Nanoparticle Synthesis & Characterization

Under the supervision of Professor Paul Santerre (Institute of Biomedical Engineering, University of Toronto) and Brian Webb (PhD Candidate, University of Toronto), we were provided with access to the MaRs research lab, where we were able to create and test PLGA nanoparticles.

Synthesized PLGA nanoparticles met all pharmaceutical benchmarks across independent batches: mean diameter 152 ± 4 nm, PDI 0.21 ± 0.02, and zeta potential −26 ± 2 mV. The diameter of nanoparticles is ideal for entry into olfactory nerve endings, the PDI confirms consistency required for reliable dosing, and the zeta potential ensures particles do not aggregate before reaching the brain. Reproducibility across all three batches confirms this is a scalable, manufacturable, and pharmaceutically viable procedure.

Conclusion

Based on these findings, NeuroRegen represents a computationally validated, disease-modifying alternative to current AD treatments. The dual-action strategy allows for superior molecular targeting, enhanced brain bioavailability, reduced systemic toxicity, and pharmaceutical reproducibility. NeuroRegen offers a safe, accessible, and scalable therapeutic platform with potential to transform AD treatment following further in-vivo and clinical validation.

Discussion and Clinical Impact

Current approved treatments for AD are highly toxic, extremely expensive, and do not effectively address the underlying neurodegeneration of AD.

Unlike traditional therapeutics, our work explores a dual-action strategy using Tropoflavin and EF24 to simultaneously target impaired BDNF-TrkB neurotrophic signaling and tau aggregation. Delivery via intranasal PLGA nanoparticles offers a targeted, cost-effective, and non-invasive alternative to conventional therapeutics, achieving substantially greater brain bioavailability than oral administration while bypassing systemic toxicity. Collectively, these findings demonstrate the viability of this approach as a novel, disease-modifying alternative that directly treats AD rather than masking its consequences.

This strategy carries profound implications for access to treatment globally. Current AD treatments can require specialized facilities, intensive clinical monitoring, and annual costs exceeding $30,000. Because of this, rural, low-income, and underserved populations are not able to receive adequate care.

A self-administered nasal spray eliminates dependence on institutional infrastructure, reducing costs by over 80x, and allows access regardless of geography or income. Regions with aging populations and critical gaps in rural healthcare infrastructure— such as Nova Scotia, which holds the highest AD mortality rate in Canada — stand to benefit most directly from access to a low-cost, safe, effective treatment with no major systemic side effects.

Together, this approach provides a new direction for equitable and effective advancement in AD therapeutics.

It is important to note that this work remains in a preliminary stage, and further in-vivo and clinical testing is required to transition from a prototype to an approved pharmaceutical.

Future Directions

While computational and preliminary in-vitro results are promising, further validation is required before clinical testing.

Future work will focus on optimizing PLGA nanoparticle formulation by varying polymer weight and lactic:glycolic acid ratios to improve encapsulation efficiency and controlled drug release. Surface modification of nanoparticles will be explored to maximize olfactory uptake while minimizing systemic absorption. In-vitro release testing can characterize drug diffusion profiles under physiological conditions.

Beyond formulation optimization, in-vitro cell viability assays using neuronal cell lines could assess direct cytotoxicity. Molecular dynamics simulations could also be extended beyond 20 nanoseconds to further validate long-term binding stability.

Firstly, we would like to thank the BASEF committee for providing us with this amazing opportunity that we will remember forever. Our mentor, Adrienne Hol provided us with tremendously valuable feedback and guidance that we are extremely grateful for.

We would also like to extend our gratitude to Dr. Paul Santerre (Professor, Institute of Biomedical Engineering, University of Toronto) and Brian Webb (PhD candidate, University of Toronto) for their clinical insights, and for providing us with valuable feedback. We would also like to thank them for supervising us and providing us with access to the MaRs research lab at the University of Toronto, where we were able to synthesize PLGA nanoparticles.

Finally, we would also like to thank our parents for their support and encouragement over the past few months.

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